We each have two number 15 chromosomes, one inherited from our mother (M.) and one inherited from our father (P, paternal). The Angelman syndrome gene (UBE3A) is located at chromosome 15, band q12, as depicted. In the brain, the Angelman gene is primarily expressed from the maternally inherited chromosome 15. The diagrams below illustrate the four known genetic mechanisms that cause Angelman syndrome. Continue Reading →

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The Angelman Syndrome Foundation is the largest non-governmental funder of Angelman syndrome-specific research. It is our hope that these funded researchers, and their collaborators and peers, will bring forth new discoveries that ultimately lead to treatments and a cure.

The ASF has partnered with leading medical and research institutions, to found the Angelman Syndrome Clinics, a “one-stop-shop” medical and psychosocial resource from birth through adulthood. Each clinic has its own unique capabilities that leverage the expertise and specialized care available from each partnering organization.

Two calls for proposals were issued in 2007: The first targeted proposal was to support research aimed at improving therapy for seizures in individuals with Angelman syndrome. Highest priority was given to pilot projects to test new ideas about the pathogenesis of, therapy for and best practices in treating seizures in individuals with Angelman syndrome.

Therapeutic effectiveness of levodopa in the treatment of seizures and motor defects using the Angelman Syndrome mouse modelDr. Edwin J. Weeber, PhD, University of South Florida, Tampa, Florida
$50,000

This grant supported a trial of levodopa-carbidopa treatment on AS mice. Levodopa is a dopamine precursor that is converted to dopamine in the brain and is commonly used as a treatment for Parkinson disease. AS mice and normal controls were treated with two different dosages of levodopa-carbidopa or placebo and subjected to tests of motor and cognitive abilities, anxiety and seizure susceptibility. Brain regions were analyzed for Dopamine and other monoamine neurotransmitter levels. Alterations in CAMKII phosphorylation (something that was discovered to be abnormal in the AS mouse model) was also examined. Behavior testing showed an improvement in motor function dependent on treatment, but did not normalize cerebellar-mediated licking behavior. Low-dose levodopa treatment partially rescued motor function but did not completely rescue AS mouse behavioral phenotypes.

There is a small amount of anecdotal experience and some neuroscience studies suggesting that levodopa might have therapeutic effect on the symptoms of AS. The Angelman mouse model is an ideal way to study this before developing any human clinical trials and that was the reason for ASF funding this project. The investigator was able to use Angelman mice to investigate effects of levodopa supplementation and in some areas no effect was demonstrated (such as on a type of synaptic activity called long-term potentiation) but in other areas, such as assessment of mouse EEG patterns, an effect was noted. The results did not reveal dramatic effects from levodopa supplementation but did identify areas worthy of further study.

ASF has supported varied initiatives to improve treatment of seizures in AS and this grant aimed at exploring alternatives to the use of the very restrictive ketogenic diet. In the low glycemic diet, the extremely high lipid content of the ketogenic diet is avoided and more carbohydrates are provided, particularly ones that are more likely to be absorbed at a slower and more stable rate. The hypothesis is that this dietary strategy will allow more stable blood glucose levels and thus improve the control of seizures. This grant has enrolled individuals under 18 years of age in an ongoing clinical study that is providing data on strategies for use of the diet in AS.

Funding for this grant enabled the largest survey ever to be conducted on AS regarding anticonvulsant drug use. This was an extensive questionnaire survey of families within and outside the United States and the results provided important information to families and physicians who seek treatment information about single anticonvulsant drugs and combination drug use for treatment of the seizure problem in AS.

The mouse model provides an ideal way to evaluate therapeutic attempts to increase UBE3A function on the otherwise silenced paternally-derived mouse chromosome. Using novel genetic engineering methods, Dr. Beaudet and his lab were able to develop a engineered mouse with genetic tags on both the paternally and maternally expressed genes, thus enabling a way of detecting more precisely whether drugs or agents are capable of improving activity of the otherwise silenced UBE3A gene. This is part of a number of studies aimed at developing novel treatment strategies for AS.

We know that individuals with AS have a propensity for a happy demeanor and often have excessive laughter. We also know that they have pro-social behaviors that are distinctive from other types of genetic conditions. This study evaluated older individuals with Angelman who could cooperate in an experiment whereby subtle regional EEG patterns were studied after certain visual cues were presented. These cues involved pictures of individuals’ faces that were happy, sad or showed other types of visual cues.

ASF foundation was proud to sponsor this research by Nobel Laureate Aaron Ciechanover who has been instrumental in characterizing the ubiquitin protein degradation system, a fundamental component of how neurons degrade or adjust proteins in order to function normally. This research focused on the DNA structure and surrounding protein regions of DNA and UBE3A in an attempt to understand how the gene is regulated and what might serve to turn on or repress activity of the gene. Dr. Ciechanover found that indeed Ring1B is a target of UBE3A. How the disruption of Ring1B ubiquitination leads to symptoms in AS is still poorly understood and more work does need to be done in this area.

It is known that UBE3A is important inside brain neurons especially at their membrane surfaces where the synapse facilitates communication between neurons. It has also been recognized that other cellular problems develop when UBE3A is defective and this laboratory identified problems in a protein synthesis and transport system called the Golgi apparatus. Inside the cells of Angelman mice, the Golgi are abnormal and swollen and the work of these investigators provided new insight into UBE3A’s relationship to other proteins in the cell.

Redesigning the ubiquitin pathway to identify the substrates of E6AP
Dr. Brian Kuhlman, PhD
University of North Carolina, Chapel Hill, North Carolina
$80,000

UBE3A function in the cell has remained elusive especially in terms of how UBE3A protein action relates to other proteins. Thus, researchers have been trying to identify “targets” (meaning proteins) that UBE3A is acting upon in order to either regulate their concentration or cause their degradation. This grant funded a unique method of providing intracellular protein tagging in hopes of identifying UBE3A targets and we learned from this project how difficult it is to identify such targets. This grant and others are part of an effort by ASF to identify UBE3A targets, increase understanding about UBE3A and promote new molecular therapeutic strategies.

It is known from brain MRI study that there are no obvious malformations associated with AS. However, it is not known if there are more subtle differences in brain development that might provide clues to the action of UBE3A or provide clues as to how some of the behavioral and other intellectual deficiencies might be related to microscopic changes in brain development. This grant involved detailed study of many aspects of brain shape and size, including study of the white matter nerve tracts by use of state-of-the-art MRI imaging. A group of individuals with AS were compared to a group of typically developing individuals. The results indicated presumptive areas of volume changes and white matter abnormalities that are deserving of further study. The investigators presented hypotheses correlating certain behavioral attributes with abnormalities observed from the brain imaging studies.

Importance of UBE3A for experience-dependent modifications of cortical synapses
Dr. Benjamin D. Philpot, PhD
University of North Carolina School of Medicine, Chapel Hill, North Carolina
$70,000

One way to understand brain abnormalities in those with AS is to actually study individual neurons using state-of-the-art micro-testing methods, for example, measure directly the electrical activities associated with function of the synapse in a single neuron. This technique requires great technical skill and that is the basis of this grant to Dr. Philpot and his colleagues who have experience in understanding and measuring electrical activity of neurons. Studies from this grant provided direct evidence of how neurons can change based on experience (e.g., show neuronal plasticity) and these studies have set the stage for more important work demonstrating in the living Angelman mouse how neurons undergo developmental changes in response to different environmental changes.

The role of UBE3A in development of excitatory-inhibitory balance in neocortex
Dr. Michael P. Stryker, PhD
University of California San Francisco School of Medicine, San Francisco, California
$80,000

The work in this grant extended our knowledge of brain regions that are affected when UBE3A is disrupted. Using the mouse model and studying the visual and brain cortex responses of each eye, this investigator and his laboratory were able to demonstrate how neurons in the visual cortex respond to the imprinting signals of UBE3A and adapt under different circumstances of eye closure and opening. This work, and the work of Dr. Philpot, expands our knowledge of UBE3A’s action in the brain and how neurons adjust to changing circumstances and it demonstrates how UBE3A is involved in neural plasticity, a process so important to the acquisition of learning.

The work related to this grant extended the long term interest of Dr. Summers in studying how individuals with AS learn and how their behaviors change based on carefully designed behavioral analysis methods in a structured environment. Most importantly, her work has led to development of a standardized and easy to implement assessment battery, specific to AS, which will help to further study and understand learning ability in AS.

Dr. Weeber has performed crucial genetic and therapeutic studies on the AS mouse model and was instrumental in conducting one of the first experiments that rescued many of the neurophysiological and behavioral problems of the Angelman mouse. To help build upon this work, ASF provided grant funding to explore a number of potential therapeutic strategies using the Angelman mouse model. These strategies included novel attempts at gene therapy and experiments to explore new protein regulators of UBE3A function. His lab studied neurophysiological properties of hippocampal neurons and also evaluated more global brain regions to evaluate results of these studies. Work from this grant, as well as evidence from other lines of research, show that imprinting of UBE3A in neurons in the mouse brain is quite widespread if not globally distributed.